UCI ADRC Overall Project Summary/Abstract The central theme of the University of California, Irvine Alzheimer's Disease Research Center (UCI ADRC) is to identify, quantify, and validate factors that influence the risk of Alzheimer's disease (AD) across the lifespan. Given its diverse and multifactorial nature, it is critical to understand the etiology and progression of this insidious brain disorder at multiple dimensions, including clinically and neuropathologically, and to employ novel scientific approaches so that we can advance knowledge and better diagnose, prevent and cure the disease. The UCI ADRC has a strong history of integrating basic, clinical, and translational science to gain insights into AD pathogenesis and to help meet some of the goals of the National Alzheimer's Project Act. First, our Center has a distinguished record of studying the disease in diverse patient cohorts: Uniform Data Set (UDS) Cohort, which includes cognitively normal individuals and individuals with mild cognitive impairment (prodromal AD); adults with Down syndrome, representing the largest genetically at-risk population for AD; and 90+, which show great disparity between AD pathology and cognitive loss and are among the oldest group of individuals to develop AD. Together, these cohorts enable interrogation of important novel questions related to age, susceptibility and resilience, using innovative outcomes ranging from in vivo biomarker characterization to modern pathological outcomes such as post-mortem imaging and microglial staining. Second, the UCI ADRC has a history of innovation that has helped advance the field; the development of the nation's first induced pluripotent stem cell bank for AD as part of the ADRC network and our recently established Consent-to- Contact recruitment registry are recent examples of this innovation. Third, our Center continues to evolve. Given the expertise, productivity, and resources devoted the study of special populations at UCI, we have initiated two Special Populations Cores, one focused on Down syndrome and one focused on the oldest old (90+). These Cores will interact with the other cores of the ADRC to produce novel data and resources available to ADRC investigators, including through our newly established Biomarker Core. Finally, we have established a new Research and Education Component in this proposal, which harnesses the long-standing passionate commitment to training the next generation of clinicians and scientists at UCI. In sum, the UCI ADRC brings energetic and innovative multi-dimensional and multidisciplinary approaches toward addressing the national epidemic of AD.